Salvianolic acid B as an anti-emphysema agent II: In vivo reversal activities in two rat models of emphysema

摘要

Emphysema progressively destroys alveolar structures, leading to disability and death, yet remains irreversible and incurable to date. Impaired vascular endothelial growth factor (VEGF) signaling is an emerging pathogenic mechanism, thereby proposing a hypothesis that VEGF stimulation/elevation enables recovery from alveolar structural destruction and loss of emphysema. Our previousin vitrostudy identified that salvianolic acid B (Sal-B), a polyphenol of traditional Chinese herbal danshen, stimulated lung cell proliferation and migration, and protected against induced lung cell death, by virtue of signal transducer and activator of transcription 3 (STAT3) activation and VEGF stimulation/elevation. Thus, this study examined Sal-B forin vivotherapeutic reversal ofestablishedemphysema in two rat models. Emphysema was induced with porcine pancreatic elastase (PPE) and cigarette smoke extract (CSE), and established by day 21. Sal-B was then spray-dosed to the lung three times weekly for three weeks. Functional treadmill exercise endurance; morphological airspace enlargement and alveolar destruction; apoptosis, cell proliferation and tissue matrix proteins; phosphorylated STAT3 (pSTAT3) and VEGF expressions; neutrophil accumulation; and lipid peroxidation were determined. In both models, Sal-B at 0.2?mg/kg significantly reversed impaired exercise endurance by 80 and 64%; airspace enlargement [mean linear intercept (MLI)] by 56 and 67%; and alveolar destructive index (%DI) by 63 and 66%, respectively. Induced apoptosis activity [cleaved caspase-3] was normalized by 94 and 82%; and cell proliferation activity [proliferative cell nuclear antigen (PCNA)] was stimulated by 1.6 and 2.1-fold. In the PPE-induced model, Sal-B reduced induction of lung's matrix metalloproteinase (MMP)-9 and MMP-2 activities by 59 and 94%, respectively, and restored pSTAT3 and VEGF expressions to the healthy lung levels, while leaving neutrophil accumulation unchecked [myeloperoxidase (MPO) activity]. In the CSE-induced model, Sal-B elevated pSTAT3 and VEGF expressions both by 1.8-fold over the healthy lung levels, and normalized induced lipid peroxidation [malondialdehyde (MDA) activity] by 68%. These results provide anin vivoproof-of-concept for Sal-B as one of the first anti-emphysema agents enabling reversal of alveolar structural destruction and loss via local lung treatment by virtue of its STAT3 activation and VEGF stimulation.